Agents for potentiating the effects of antitumor agents and combating multiple drug resistance

ABSTRACT

Potentiating agents which enhance the efficacy of antineoplastic agents are disclosed. The potentiating agents disclosed are dibenz[b,e]oxepins such as doxepin.

This is is a divisional of application Ser. No. 07/539,838, filed Jun.18, 1990, now U.S. Pat. No. 5,300,282 and of United Kingdom Patent8914061.0 granted Jun. 20, 1989.

FIELD OF THE INVENTION

The present invention relates to the use of dibenz-[b,e]oxepin compoundsas adjuvant chemotherapy for neoplasias resistant to multiple drugs. Thepresent invention also relates to the use of such compounds as an agentfor enhancing the therapeutic effect of multiple antitumor agents.

BACKGROUND OF THE INVENTION

Complete cures of various tumors like leukemias, lymphomas and solidtumors by the use of chemotherapeutic agents are rare because ofheterogeneous sensitivity of tumor cells to each antitumor agent. Cancerchemotherapy also fails because of intrinsic resistance of tumors tomultiple drug therapies. In other cases, a tumor may become resistant tothe antitumor agents used in a previous treatment. The therapeuticeffects of these agents are then eliminated. An even graver problem isthat recurrent cancers are resistant not only to the cancer suppressantsused in previous treatments, but also manifest resistance to otherantitumor agents, unrelated to the agent used previously either bychemical structure or by mechanism of action. These phenomenon arecollectively referred to as multiple drug resistance (mdr) andcontribute widely to cancer treatment failures in the clinic.

The major documented cause of multiple drug resistance is overexpressionof a membrane glycoprotein (the multiple drug transporter) responsiblefor pumping structurally diverse antitumor drugs from cells. See D.Houseman et al., A Molecular Genetic Approach to the Problem of DrugResistance in Chemotherapy, 504-517 (1987) (Academic Press, Inc.); R.Fine and B. Chabner, Multidrug Resistance, in Cancer Chemotherapy 8,117-128 (H. Pinedo and B. Chabner eds. 1986).

Tumor cells expressing elevated levels of the multiple drug transporteraccumulate far less antitumor agents intracellularly than tumor cellshaving low levels of this enzyme. The degree of resistance of certaintumor cells has been documented to correlate with both elevatedexpression of the drug transporter and reduced accumulation of antitumordrugs. See M. Gottesman and I. Pastan, J. Biol. Chem. 263, 12163 (1988);see also A. Fojo et al., Cancer Res. 45, 3002 (1985). This form ofmultiple drug cross-resistance involves agents derived from naturalproducts, such as the vinca alkaloids, the anthracyclines, theepipodophyllotoxins, actinomycin D and plicamycin. See I. Pastan and M.Gottesman, New England J. Med. 1388, 1389 Table 1 (May 28, 1987).

Adenocarcinomas derived from adrenal, kidney, liver, small intestine,and colon tissue are notorious for exhibiting inherent cross-resistanceto chemically unrelated chemotherapeutic agents. See M. Gottesman and I.Pastan, supra at 12165; see also A. Fojo et al., J. Clin. Oncol. 5, 1922(1987). These tissues normally express higher levels of the multidrugtransporter. Other tumors documented to express high levels of themultidrug transporter include pancreatic, carcinoid, chronic myelogenousleukemia in blast crisis, and non-small cell lung carcinoma. Tumorsdocumented to initially be drug-sensitive but to then become drugresistant include neuroblastoma, pheochromocytoma, acute lymphocyticleukemia in adults, acute nonlymphocytic leukemia in adults, nodularpoorly differentiated lymphoma, breast cancer and ovarian cancers. It isestimated by the National Cancer Institute that approximately half amillion tumor samples a year will be drug resistant because of aberrantlevels of expression of the multidrug transporter. See L. Goldstein etal., Expression of Multidrug Resistance Gene in Human Cancers, J.National Cancer Institute 81, 116 (1988).

Elevated levels of expression of the mdr drug transporter in thesetumors would lead to reduced intracellular levels of antitumor agents inthe tumor and would cause suppression of chemotherapeutic efficacy.Tumors having elevated levels of the multiple drug transporter wouldrequire therapeutic doses of cancer suppressants far in excess of tumorsexhibiting lower levels of the mdr drug transporter. Agents that inhibitthe active efflux of antitumor agents by the drug transporter or agentsthat potentiate the efficacy of chemotherapeutic agents would enhancethe activity of various antitumor agents on tumor cells. As a result ofthe present inventor's study, it has unexpectedly been found that whenthe agents disclosed herein are used together with an antitumor agent,they enhance the therapeutic effect of the antitumor agent.

A number of agents used clinically as calcium channel-blockers,calmodulin inhibitors and antiarrhythmic agents promote the activity ofantitumor agents against resistant tumor cells, see Tsuruo et al.,Cancer Res. 44, 4303 (1984); 43, 2267 (1983). Verapamil, caroverine,clomipramine, trifluoperazine, prenylamine, diltiazem, nicardipine, andquinidine enhance the activity of antitumor agents against resistantsublines of murine leukemia cells. Most agents potentiating the activityof antitumor agents are calcium antagonists, and the seriouscardiotoxicities that arise during treatment have limited their clinicalusefulness. While the inventor does not wish to be bound by any theoryof operation for the present invention, it is noted that the agentsdisclosed herein are not known to have calcium antagonism. They have,however, been found to elevate the intracellular concentration ofantineoplastic drugs in tumor cells overexpressing the multiple drugtransporter. Sensitization of drug resistant tumors and elevation ofintracellular antitumor drug concentrations probably occur by amechanism different from calcium antagonism.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an agent for enhancingthe therapeutic effect of an antineoplastic agent by administering to asubject harboring a tumor a compound of Formula (I) below or apharmaceutically acceptable salt thereof (hereafter referred to as the"potentiating agent") ##STR1## wherein:

R₁ is --CH₂ CH₂ --, --CH₂ O--, --OCH₂ --, --NHCH₂ --, or --CH₂ NH--;

X is hydrogen or halogen (e.g., fluorine, chlorine, bromine) attached atthe 7, 8, 9 or 10 position;

Y is hydrogen or halogen (e.g., fluorine, chlorine, bromine) attached atthe 1, 2, 3 or 4 position;

n is 0 to 3;

each of p and q is 1 to 4; and

R₂ and R₃ independently are hydrogen, or C₁₋₄ alkyl, or together withthe nitrogen atom form a nitrogen-containing heterocyclic ring havingfour to six ring members.

Preferably:

R₁ is --CH₂ CH₂ --, --CH₂ O--, or --OCH₂ --;

p and q are 1;

n is 1 or 2; and

R₂ and R₃ independently are hydrogen, or C₁₋₄ alkyl, or taken togetherwith the nitrogen atom form pyrrolidino.

Another aspect of the present invention is a method of increasing thesensitivity of a tumor to an antineoplastic agent when the tumor isresistant to the antineoplastic agent by administering to the subjectharboring the resistant tumor a potentiating agent concurrently with anantineoplastic agent. Resistance to the antineoplastic agent may (a) bean intrinsic property of the tumor or (b) develop in response to priortreatment with the same antineoplastic agent or another antineoplasticagent capable of selecting for multi-drug resistance.

Another aspect of the present invention is a method of selectivelyinhibiting the growth of tumor cells in a subject in need of suchtreatment by concurrently administering to the subject an antineoplasticagent and a potentiating agent. The potentiating agent is administeredin an amount effective to (a) reduce the amount of the antineoplasticagent required to achieve the same growth inhibiting effect on the tumorcells by the antineoplastic agent achieved without the concurrentadministration of the potentiating agent; or (b) inhibit the developmentof multiple drug resistance in the tumor cells after treatment with theantineoplastic agent over time.

Another aspect of the present invention is a method of inhibitingmultiple drug resistance in a subject in need of such treatment byadministering the subject a potentiating agent in an amount effective tocombat multiple drug resistance.

Another aspect of the present invention is the use of the compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for inhibition of multiple drug resistancein tumors.

Another aspect of the present invention is a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, in combination with a pharmaceutically acceptable carrier,with the proviso that X and Y do not independently represent hydrogen,fluorine or chlorine when R₁ is --CH₂ O--, n is 2 and R₂ and R₃represent hydrogen or C₁₋₄ alkyl.

Another aspect of the present invention is novel compounds comprisingcompounds of Formula (I), or the pharmaceutically acceptable saltsthereof, with the provisos that: (a) when one of X and Y represent haloat the 2, 3, 8 or 9 position the other is not hydrogen; and (b) X and Ydo not independently represent chlorine, fluorine or hydrogen when R₁ is--CH₂ O--, n is 2 and R₂ and R₃ are hydrogen or C₁₋₄ alkyl.

Another aspect of the present invention is a pharmaceutical formulationcomprising a potentiating agent as disclosed herein in combination withan antineoplastic agent, in a pharmaceutically acceptable carrier.

Another aspect of the present invention is the use of both the newpharmaceutical compositions disclosed above and the novel compoundsdisclosed above as antiasthmatic and antihistaminic agents.

DETAILED DESCRIPTION OF THE INVENTION

Potentiating agents exemplary of the present invention include:

(A) (Z)-3-(2-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine trihydrochloride;

(B) (E)-3-(2-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine 3/2 hydrochloride;

(C) (Z)-3-(9-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine;

(D) (Z)-3-(4-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine;

(E) (Z)-3-(3-Bromo-6,11-dihydrodibenz[b,e]oxepin-ylidene)-N,N-dimethylpropylamine;

(F) (Z)-1-[2-(2-Bromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)ethyl]pyrrolidine;

(G) (Z)-1-[3-(2-Bromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)propyl]pyrrolidine;

(H) (Z)-1-[2-(6,11-Dihydrodibenz[b,e]oxepin-1-ylidene)ethyl]pyrrolidinehydrochloride;

(I) (Z)-3-(2-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-diethylpropylamine;

(J)1-[2-(4-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidine)-ethyl]pyrrolidine60% Z, 40% E;

(K) (E)-1-[3-(2-Bromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)propyl]pyrrolidine;

(L) (E)/(Z) -3-(8-Bromo-6,11-dihydrodibenz[b,e]-oxepine-11-ylidene)-N,N-dimethylpropylamine (80% Z:20% E);

(M) (Z)-1-[3-(9-Bromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)propyl]pyrrolidine;

(N) (E) -3-(2-Bromo-6,11-dihydrodibenz [b,e]oxepin-11-ylidene)-N,N-diethylpropylamine;

(O) (Z)-1-[3-(2,9-dibromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)propyl]pyrrolidine;

(P) (E)-3-(2-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-ylidine)-N,N-dimethylpropylamine;

(Q) (Z)-3-(2-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine;

(R) (E)-1-[3-(2,9-dibromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)propyl]pyrrolidine;

(S) (E)-1-[3-(2-fluoro-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)propyl]pyrrolidine;

(T) (Z)-1-[3-(2-fluoro-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)propyl]pyrrolidine;

(U) (Z)-3-(2,9-Dibromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylamine;

(V) (E)-3-(2,9-Dibromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylamine 0% and

(Z) -isomer 30%; and

(W) doxepin.

The foregoing compounds are prepared in the manner described below, orare prepared by procedures which will be apparent to those skilled inthe art. Compounds (A) and (B) above are disclosed in European PatentApplication Publication Number 0 214 779 to L. Lever and H. Leighton, atpage 6.

A compound of Formula (I) may be prepared via the Wittig method (see,e.g., U.S. Pat. Nos. 3,354,155 and 3,509,175) by reaction of a compoundof Formula (II) below with a Wittig reagent. ##STR2## The Wittigreagent, (C₆ H₅)₃ P═CH(CH₂)_(n) NR₂ R₃, is prepared by reacting acompound of the formula (C₆ H₅)₃ PCH₂ (CH₂)_(n) NR₂ R₃ Br, with a strongbase, such as sodium hydride or C₁₋₆ alkyl lithium, in a suitable inertsolvent, such as tetrahydrofuran or dimethoxyethane, at or near roomtemperature.

A compound of Formula (I) also may be prepared via the Grignard reaction(see, e.g., Belg U.S. Pat. No. 623,259) in which a Grignard reagent,i.e., R² R³ NCH₂ CH₂ CH₂ Mg X, where X is a halogen atom, is reactedwith a compound of Formula (II), followed by dehydration with a strongacid.

Compounds of Formula (I) may be prepared from other compounds of Formula(I) by the exchange of halogens thereon. One method for halogen exchangeis the Finkelstein halide interchange reaction. Usually, the interchangeof a chlorine or bromine of aromatic rings with iodine is carried out byuse of a metal iodide such as cuprous iodide, or with fluorine by use ofa metal fluoride such as silver(I) fluoride in a solvent such aspyridine or quinoline or N,N-dimethylformamide with heat. A bromocompound may be converted to its corresponding chloro analogue by eitheruse of a metal chloride such as cuprous chloride or lithium chloride ina solvent such as N,N-dimethylformamide, picoline or dimethylsulfoxidewith heat (100°-103° C.), or by chlorine in radical form by radiation attemperatures of 30°-50° C. A bromo compound may also be converted to itsiodo analogue by exchanging the bromine for a metal using a metal alkylsuch as n-butyllithium in a ethereal solvent such as diethyl ether ortetrahydrofuran at low temperature (e.g., -78° C.), followed by reactingthe metalated species with iodine cold or at room temperature or withheat to accomplish the iodination.

Compounds of Formula (I) may be prepared from compounds of Formula(III), wherein R₁, R₂, and R₃ are as given above, by directhalogenation. ##STR3## Halogenation is preferably carried out withchlorine or bromine in an inert solvent such as acetic acid, methanol,or carbon tetrachloride. In nonpolar solvents, the reaction may becatalyzed by added reagents such as hydrogen chloride andtrifluoroacetic acid. The catalytic effect of trace amounts of Lewisacids added to the reaction solution may be employed, such as zincchloride or ferric chloride in chlorinations and metallic iron, whichgenerates FeBr₃ often added to Bromination mixtures. See, e.g., F. Careyand R. Sundberg, Advanced Organic Chemistry Part B: Reactions andSynthesis, 260-63 (1977).

A preferred category of multiple drug resistant tumor cells to betreated by the method of the present invention are multiple drugresistant cells characterized by the multidrug transporter-mediatedpumping of antineoplastic agents out of the tumor cells. The multidrugtransporter protein is described in M. Gottesman and I. Pastan, supra.Thus, tumor cells treated by the present invention are preferably thosecharacterized by (a) the expression of the multidrug transporter proteinat high levels, or (b) the ability to express the multidrug transporterprotein upon selection by an antineoplastic agent.

Exemplary of tumor cells which express the multidrug transporter at highlevels (intrinsically resistant cells) are adenocarcinoma cells,pancreatic tumor cells, carcinoid tumor cells, chronic myelogenousleukemia cells in blast crisis, and non-small cell lung carcinoma cells.

Exemplary of tumor cells having the ability to express the multidrugtransporter protein upon selection by an antineoplastic agent areneuroblastoma cells, pheochromocytoma cells, adult acute lymphocyticleukemia cells, adult acute nonlymphocytic leukemia cells, nodularpoorly differentiated lymphoma cells, breast cancer cells and ovariancancer cells.

A preferred group of tumor cells for treatment in the present inventionare the adenocarcinomas, including adenocarcinomas of adrenal, kidney,liver, small intestine and colon tissue, with kidney adenocarcinomacells particularly preferred.

Preferred antineoplastic agents for use in the present invention arethose to which multidrug transporter-mediated multiple drug resistantcells develop resistance. Exemplary of such antineoplastic agents arevinca alkaloids, epipodophyllotoxins, anthracycline antibiotics,actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine,cytochalasin B, emetine, maytansine, and amsacrine (or "mAMSA").Preferred are vinca alkaloids, epipodophyllotoxins, anthracycleneantibiotics, actinomycin D, and plicamycin.

The vinca alkaloid class is described in Goodman and Gilman's ThePharmacological Basis of Therapeutics, 1277-1280 (7th ed. 1985)(hereafter "Goodman and Gilman"). Exemplary of vinca alkaloids arevincristine, vinblastine, and vindesine.

The epipodophyllotoxin class is described in Goodman and Gilman, supraat 1280-1281. Exemplary of epipodophyllotoxins are etoposide, etoposideorthoquinone, and teniposide.

The anthracycline antibiotic class is described in Goodman and Gilman,supra at 1283-1285. Exemplary of anthracycline antibiotics aredaunorubicin, doxorubicin, mitoxantraone, and bisanthrene. Daunorubicinand doxorubicin are preferred.

Actinomycin D, also called Dactinomycin, is described in Goodman andGilman, supra at 1281-1283. Plicamycin, also called mithramycin, isdescribed in Goodman and Gilman, supra at 1287-1288.

The phrase "concurrently administering," as used herein, means that theantineoplastic agent and the potentiating agent are administered either(a) simultaneously in time (optionally by formulating the two togetherin a common carrier), or (b) at different times during the course of acommon treatment schedule. In the latter case, the two compounds areadministered at times sufficiently close for the potentiating agent toenhance the selective growth-inhibiting action of the antineoplasticagent on the tumor cells.

Subjects to be treated by the method of the present invention includeboth human and animal (e.g., dog, cat, cow, horse) subjects, and arepreferably mammalian subjects.

The potentiating agent is administered in an amount effective to enhancethe efficacy of the antineoplastic agent. The potentiating agent ispreferably administered in a total amount per day of not more than about50 mg/kg body weight, more preferably not more than about 25 mg/kg, andmost preferably not more than about 5 mg/kg. With respect to minimumdose, the potentiating agent is preferably administered in a totalamount per day of at least about 0.01 mg/kg, more preferably at leastabout 0.1 mg/kg, and most preferably at least about 1 mg/kg. Thepotentiating agent may be administered once or several times a day.

As noted above, the compounds of Formula (I) may be administered per seor in the form of a pharmaceutically acceptable salt. When used inmedicine, the salts of the compounds of Formula (I) should be bothpharmacologically and pharmaceutically acceptable, butnon-pharmaceutically acceptable salts may conveniently be used toprepare the free active compound or pharmaceutically acceptable saltsthereof and are not excluded from the scope of this invention. Suchpharmacologically and pharmaceutically acceptable salts include, but arenot limited to, those prepared from the following acids: hydrochloric,hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic,p-toluenesulfonic, tartaric, citric, isethionic, methanesulphonic,formic, malonic, succinic, naphthalene-2-sulphonic and benzenesulphonic.Also, pharmaceutically acceptable salts can be prepared as alkalinemetal or alkaline earth salts, such as sodium, potassium or calciumsalts of the carboxylic acid group. Thus, the present invention alsoprovides pharmaceutical formulations, both for veterinary and for humanmedical use, which comprise the potentiating agent together with one ormore pharmaceutically acceptable carriers thereof and optionally anyother therapeutic ingredients. The carrier(s) must be pharmaceuticallyacceptable in the sense of being compatible with the other ingredientsof the formulation and not unduly deleterious to the recipient thereof.

Pharmaceutical formulations of the present invention may optionallyinclude an antineoplastic agent, preferably an agent as described above.Such a formulation is useful for concurrently administering anantineoplastic agent and the potentiating agent in a method as describedabove.

The formulations include those suitable for oral, rectal, topical,nasal, ophthalmic or parenteral (including subcutaneous, intramuscularand intravenous) administration. Formulations suitable for oral andparenteral administration are preferred.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into association with a liquidcarrier, a finely divided solid carrier, or both, and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the potentiatingagent as a powder or granules; or a suspension in an aqueous liquor ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine, with the active compound being in afree-flowing form such as a powder or granules which is optionally mixedwith a binder, disintegrant, lubricant, inert diluent, surface activeagent or dispersing agent. Molded tablets comprised of a mixture of thepowdered active compound with a suitable carrier may be made by moldingin a suitable machine.

A syrup may be made by adding the active compound to a concentratedaqueous solution of a sugar, for example sucrose to which may also beadded any accessory ingredient(s). Such accessory ingredient(s) mayinclude flavorings, suitable preservatives, an agent to retardcrystallization of the sugar, and an agent to increase the solubility ofany other ingredient, such as a polyhydric alcohol, for example glycerolor sorbitol.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound, which ispreferably isotonic with the blood of the recipient.

Nasal spray formulations comprise purified aqueous solutions of theactive compound with preservative agents and isotonic agents. Suchformulations are preferably adjusted to a pH and isotonic statecompatible with the nasal mucous membranes.

Formulations for rectal administration may be presented as a suppositorywith a suitable carrier such as cocoa butter, or hydrogenated fats orhydrogenated fatty carboxylic acids.

Ophthalmic formulations are prepared by a similar method to the nasalspray, except that the pH and isotonic factors are preferably adjustedto match that of the eye.

Topical formulations comprise the active compound dissolved or suspendedin one or more media such as mineral oil, petroleum, polyhydroxyalcohols or other bases used for topical pharmaceutical formulations.The addition of other accessory ingredients, vide infra, may bedesirable.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders,disintegrants, surface active agents, thickeners, lubricants,preservatives (including antioxidants) and the like.

The new compounds and new pharmaceutical compositions of this inventionhave antiallergic activity and may be used for the same indications asclinically used antiasthmatic compounds, namely to help to controlbronchoconstriction or bronchospasm characteristic of allergic asthmaand exercise induced asthma and the symptoms of bronchoconstriction andbronchospasm resulting from acute or chronic bronchitis. The compoundsand compositions are believed to inhibit the release of autocoids (i.e.,histamine, serotonin and the like) from mast cells and to inhibitdirectly the antigen-induced production of histamine. Thus, they may beclassified as mast cell stabilizers with antihistaminic action.

The new compounds and new pharmaceutical compositions of this inventionhave antihistamine activity, and may be used for the same indications asclinically used antihistamines, namely to relieve detrimental symptoms(caused by histamine release) of nasal stuffiness due to colds andvasomotor rhinitis and for the symptomatic control of allergicconditions including nasal allergy, perennial rhinitis, urticaria,angloneurotic oedema, allergic conjunctivitis, food allergy, drug andserum reactions, insect bites and stings and desensitizing reactions.The compounds and compositions may also be used in conditions responsiveto their antipruritic activity including allergic dermatoses,neurodermatitis, anogenital pruritus, and pruritus of non-specificorigin such as eczema, and of specific cause such as chickenpox,photosensitivity and sunburn. The present invention therefore provides amethod for the symptomatic treatment of allergic conditions by theadministration of an effective amount of the new compounds andcompositions. The present invention also provides a method for theantagonism of endogenously released histamine by the administration ofan effective amount of the new compounds and compositions.

The amount of active compound required for antiasthmatic orantihistaminic use will vary with the compound chosen, the route ofadministration and the condition of mammal undergoing treatment, and isultimately at the discretion of the physician. A suitable oral dose ofthe active compound for a mammal is in the range of from 0,003 to 1.0milligram per kilogram body weight per day; preferably from 0.04 to 0.24milligram per kilogram.

The desired daily dose is preferably presented as from one to sixsub-doses administered at appropriate intervals throughout the day asneeded. Where three sub-doses are employed, each will preferably lie inthe range of from 0.014 to 0.08 milligrams per kilogram body weight; forexample, a typical sub-dose of such a compound for a human recipient isbetween 1 and 20 milligrams, for example, or 8 milligrams.

The following Examples are provided to illustrate the present invention,and should not be construed as limiting thereof. Temperatures are givenin degrees Celsius unless otherwise indicated.

EXAMPLE 1(E)/(Z)-1-[3-(2-Bromo-6,11-dihydrodibenz-[b,e]oxepin-11-ylidene)propyl]pyrrolidine(Compounds K and G)

Anhydrous 3-(N-pyrrolidinyl)propyltriphenylphosphonium bromidehydrobromide (24 g, 45 mmole) was suspended in 650 ml drytetrahydrofuran and 90 mmole of n-butyl in hexane (1.6M) was addeddropwise at 0° C. under a nitrogen atmosphere during a 30-minute period.After an additional ten minutes,2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, mmole), which wasprepared as described in U.S. Pat. No. 4,282,365, in 100 mL drytetrahydrofuran was added slowly to the deep red solution and thereaction mixture was then refluxed for 18 hours. The reaction mixturewas poured onto ice water, and the mixture was extracted with diethylether. The ether layer was concentrated under reduced pressure and theresidue was chromatographed on a silica gel column (Waters Associates -Prep 500) with ethyl acetate/methanol (9:1) to give the pureZ-bromopyrrolidine (1.10 g) as a yellow solid, mp 103°-104° C. pmr(DMSO-d₆) δ:7.24-7.35 (m, 6H, aromatic H); 6.74 (d, J=8.4 Hz, 1H, H₄);5.74 (t, 1H, CH═); 5.20 (br s, 2H, ArCH₂ O); 2.56-2.69 (m, 8H, CH₂ C═and 3 N--CH₂); 1.81 (m, 4H, 2 CH₂).

Analysis: Calculated for C₂₁ H₂₂ BrNO: C, 65.63; H, 5.77; N, 3.64.

Found: C, 65.69; H, 5.80; N, 3.63.

This also offered the pure E-bromopyrrolidine and converted to itshydrochloride salt (0.11 g) as a white solid, mp 203°-205° C. pmr(DMSO-d₆) δ:7.29-7.46 (m, 6H, aromatic H); 6.70 (d, J=8.8 Hz, 1H, H₄);6.09 (t, 1H, CH═); 5.20 (br s, 2H, ArCH₂ O);4.31-1.02 (m, 12H, 3NCH₂ and3CH₂).

Analysis: Calcd. for C₂₁ H₂₂ BrNO.0.05 H₂ O.1.3 HC1: C, 58.30; H, 5.45;N, 3.24.

Found: C, 58.21; H, 5.35, N, 3.24.

EXAMPLE 2

(E)/(Z)-1-[2-(2-Bromo-6,11-dihydrodibenz-[b,e]oxepin-11-ylidene)ethyl]pyrrolidine(Compound F)

Anhydrous 2 -(N-pyrrolidinyl)-ethyltriphenylphosphonium bromide (10 g,45 mmole), 48 mmole of n-butyl lithium in hexane, and2-bromo-6,11-dihydrodibenz[b,e]-oxepin-11-one (5 g, 35 mmole) werereacted in 300 mL dry tetrahydrofuran by the procedure in Example 1,Step a. This provided the pure Z-isomer (1.76 g) as a light brown solid,mp 108°-109° C. pmr (DMSO-d₆) δ: 7.28-7.50 (m, 6H, aromatic H); 6.80 (d,J=8.8 Hz, 1H, H₄); 5.82 (t, 1H, HC═); 5.20 (s, 2H, ArCH₂ O); 3.29 (m,2H, NCH₂ C═); 2.50 (m, 4H, 2NCH₂); 1.70 (m, 4H, 2CH₂).

Also, the pure (E)-isomer was obtained as a light-brown oil. pmr(DMSO-d₆) δ: 7.22-7.51 (m, 6H, aromatic H); 6.79 (d, J=8.8 Hz, 1H, H₄);6.16 (t, 1H, HC=); 5.40-5.50 (br s, 2H, ArCH₂ O); 3.0 (m, 2H, NCH₂ C═);2.36 (m, 4H, 2NCH₂); 1.64 (m, 4H 2CH₂).

Analysis: Calculated for C₂₀ H₂₀ BrNO: C, 64.87; H, 5.44; N, 3.78.

Found (Z-isomer): C, 64.83; H, 5.49; N, 3.75.

Found (E-isomer): C, 64.79; H, 5.45; N, 3.77.

EXAMPLE 3

(E)/(Z)-3-(2-Bromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)-N,N-diethylpropylamine (Compounds I and N)

Anhydrous 3-(diethylamino)propytriphenylphosphonium bromide hydrobromide(15 g, 28 mmole), 56 mmole of n-butyl lithium in hexane (1.6M), and2-bromo-6,11-dihydrodibenz [b,e]-oxepin-11-one (8.1 g, 28 mmole) werereacted in 350 mL dry tetrahydrofuran by the procedure in Example 1,Step a. This provided a (Z)/(E) (90:10) isomeric product as a brown oil.pmr (DMSO-d₆) δ: 7.22-7.51 (m, 6H, aromatic H); 6.78 (d, J=8.8 Hz, H4 of90% Z); 6.68 (d, J=8.8 Hz, H₄ of 10% of E); 6.19 (t, CH═ of 10% E); 5.73(t, CH═ of 90% Z); 5.20 (br s, 2H, ArCH₂ O); 2.30-2.60 (m, 8H, 4 CH₂);0.94 (t, 6H, 2 CH₃ of 90% Z); 0.88 (t, 6 H, 2 CH₃ of 10% E) .

Analysis: Calculated for C₂₁ H₂₄ BrNO: C, 65.29; H, 6.26; N, 3.63; Br,20.68.

Found: C, 65.27; H, 6.26; N, 3.60; Br, 20.59.

EXAMPLE 4

(E)/(Z)-3-(2-Fluoro-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylamine (Compounds Q and P)

Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromidehydrobromide (35 g, 0.07 mole), 0.14 mole of n-butyl lithium in hexane(1.6M), and 2-fluoro-6,11-dihydrodibenz [b,e]oxepin-11-one (12 g, 0.05mole), which was prepared as described in European patent applicationNo. EP 38,564, were reacted in 800 mL dry tetrahydrofuran by theprocedure of Example 1, Step a. This gave pure Z-isomer (0.67 g) mp47°-48° C. pmr(DMSO-d₆) δ: 6.81-7.37 (m, 7H, aromatic H), 5.73 (t, 1H,CH═), 5.14 (br s, 2H, ArCH2O), 2.37-2.51 (m, 4H, 2CH₂), 2.09 (s, 7H,N(CH₃)₂). It also offered the pure E-isomer (1.70 g), mp 44°-45° C. pmr(DMSO-d₆) δ: 6.68-7.49 (m, 7H, aromatic H), 6.08 (t, 1H, CH═), 5.20 (brs, 2H, ArCH₂ O), 2.19-2.35 (m, 4H, 2CH₂), 2.01 (s, 7H, N(CH₃)₂) .

Analysis: Calculated for C₁₉ H₂₀ FNO.0.10 H₂ O=299.17: C, 76.26; H,6.81; N, 4.68.

Found: (Z-isomer): C, 76.20; H, 6.83; N, 4.76.

Found: (E-isomer): C, 76.14; H, 6.80; N, 4.69.

EXAMPLE 5

(E)/(Z)-1-[3-(2-Fluoro-6,11-dihydrodibenz[[b,e]oxepin-11-ylidene)-propyl]pyrrolidine(Compounds S and T)

Anhydrous 3-(N-pyrrolidinyl)propyltriphenylphosphonium bromidehydrobromide (35 g, 0.07 mole), 0.14 mole of n-butyl lithium in hexane(1.6M), and 2-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-one (12 g, 0.05mole), prepared as described in European Patent Application No. EP38,564, were reacted in 800 mL dry tetrahydrofuran by the proceduredescribed in Example 1, Step a. This offered pure Z-isomer and wasconverted to its hydrochloride form (3.0 g), mp 201°-202 ° C. pmr(DMSO-d₆) δ: 6.84-7.36 (m, 7H, aromatic H), 5.72 (t, 1H, CH═), 5.18 (brs, 2H, ArCH₂ O), 3.73-1.95 (m, 12H, 3CH₂ and 3NCH₂). This also gave pureE-isomer (0.70 g), mp 77°-78° C. pmr (DMSO-d₆) δ: 6.69-7.50 (m, 7H,aromatic H), 6.10 (t, 1H, CH═), 5.15 (br s, 2H, ArCH₂ O), 1.63-2.50 (m,12H, 3CH₂ and 3NCH₂).

Analysis: Calculated for C₂₁ H₂₂ FNO.0.96 HC1.0.04 H₂ O: C, 70.23, H,6.47; N, 3.90; Cl, 9.48.

Found: (Z-isomer): C, 69.96; H, 6.68; N, 3.77; Cl, 9.36.

Calculated for C₂₁ H₂₂ FNO.0.50 H₂ O: C, 75.88; H, 6.97; N, 4.21.

Found: (E-isomer): C, 76.03; H, 6.79; N, 4.43.

EXAMPLE 6

(E)/(Z)-3-(3-Bromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylamine(Compound E)

(a) Methyl 2-(3-bromophenoxymethyl)benzoate

To a mixture of 3-bromophenol (60 g, 0.35 mole) and potassium carbonate(25 g, 0.18 mole) in 250 mL of N,N-dimethylformamide was added methylα-bromo-2-toluate (65 g, 0.28 mole). The reaction mixture was stirred atroom temperature for 18 hours, then heated on a steam bath for threehours. The mixture was poured into ice water, and the solids werecollected by filtration and washed with water to give the crude product.Analytical sample was obtained by recrystallization from methylenechloride/hexanes, m.p. 84°85° C. pmr (CDCl₃) δ: 8.0 (m, 1H, H6),6.93-7.69 (m, 7H, aromatic H), 5.47 (s, 2H, ArCH₂ O), 3.89 (s, 3H, CO₂CH₃).

Analysis: Calculated for C₁₅ H₁₃ BrO₃ : C, 56.09; H, 4.08; Br, 24.88.

Found: C, 56.20; H, 4.12; Br, 24.77

b) 2-(3-bromophenoxymethyl) benzoic acid

Methyl 2-(3-bromophenoxymethyl) benzoate (34 g) was refluxed in amixture of 100 mL of 10% sodium hydroxide and 200 mL of methanol forthree hours. The reaction mixture was concentrated under reducedpressure and water was added to the residue. The mixture was thenacidified with concentrated hydrochloric acid. Extracting the acidicsolution with ethyl acetate and then concentration of the organic layergave 2-(3-bromophenoxymethyl ) benzoic acid (35 g) m.p. 158°-159° C. pmr(CDCL₃) δ: 8.10 ()m, 1H, H₆), 6.84-7.74 (m, 7H, aromatic H), 6.16 (br s,1H, CO₂ H), 5.49 (s, 2H, ArCH₂ O).

Analysis: Calculated for C₁₄ H₁₁ rO₃ : C, 54.74; H, 3 . 61; Br, 26.02.

Found: C, 54.65; H, 3.61; Br, 26.08.

c) 3-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one

A suspension of 2-(3-bromophenoxymethyl)benzoic acid (35 g, 0.11 mole)in 100 mL of trifluoracetic anhydride containing 20 drops of borontrifluoride-ether complex was refluxed for four hours. The mixture waspoured into ice water and then extracted with diethyl ether.Concentration of ether solution under reduced pressure andchromatography of the residue on a silica gel column (Waters Associates,Prep 500) with hexane/methylene chloride (70:30) gave the pure product(14 g) , m.p. 110°-112° C. pmr (CDCL₃) δ: 8.10 (d, J=9.1 Hz, 1H, H₁),7.90 (dd, J=l.4, 7.6 H, 1H, H₁₀) 7.57 (dt, J=1.4, 7.4, 7.4 Hz, 1H, H8),7.48 (dt, J=1.4, 7.6, 7.6 Hz, 1H, H9), 7.36 (dd, J=1.3, 7.3 Hz, H, H₇),7.27 (d, J=1.8 H, 1H, H₄), 7.24 (dd, J=1.8, 9.1 Hz, 1H, H₂), 5.18 (s,2H, ARCH₂ O).

Analysis: Calculated for C₁₄ H₉ BrO₂ : C, 58.16; H, 3.14; Br, 27.64.

Found: C, 58.13; H, 3.19; Br, 27.72.

d)(E)/(Z)-3-(3-Bromo-6,11-dihydrodibenz[[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylamine

Anhydrous 3-(dimethylamino) propyltriphenylphosphonium bromidehydrobromide (24.5 g, 48.0 mmole), 6 mmole of n-butyl lithium in hexane,and 3-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 34.6 mmole) werereacted in 580 mL dry tetrahydrofuran by the procedure of Example 1,Step a. This provided a Z/E(3:1) isomeric mixture of bromoamines (6.0g). Recrystallization of half of the mixtures (3.0 g) from ethyl acetategave 1.45 g of Z-isomer of ≧93% stereoisomeric purity (assayed by'H-NMR) and converted to its hydrochloride salt as a white solid. pmr(CDCl₃) δ: 7.23-7.31 (m, 4H, aromatic H), 6.92-7.05 (m, 3H, aromatic H),5.91 (t, 1H, CH═, 7% E-isomer), 5.60 (t, 1H, CH═, 93% Z-isomer), 5.15(very br s, 2H, ArCH₂ O), 3.12 (m, 2H, CH₂), 2.99 (m, 2H, NCH.sub. 2),2.78 (s, 6H, NMe₂, 93% Z-isomer), 2.71 (s, 6H, NMe₂, 3% E-isomer).

Analysis: Calculated for C₁₉ H₂₀ BrNO.1.0 HCl: C, 57.81; H, 5.36; N,3.55.

Found: C, 57.62; H, 5.33; N, 3.54.

EXAMPLE 7

(E)/(Z)-3-(4-Bromo-6,11-dihydrodibenz [b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine (Compound D)

(a) Methyl 2-(2-bromophenoxymethyl)benzoate Methyl α-bromo-2-toluate (53g, 0.23 mole) was added to a mixture of 2-bromophenol (40 g, 0.23 mole)and potassium carbonate (42 g, 0.3 mole) in 250 mL ofN,N-dimethylformamide. The reaction mixture was stirred at roomtemperature for 18 hours, then heated on a steam bath for 3.5 hours. Themixture was poured into ice water, and the solids were collected byfiltration and washed with water to give the crude product. Ananalytical sample was obtained by recrystallization from hexane/ethylacetate (38 g, mp 73°-74° C. pmr (CDCl₃) δ: 6.58-8.05 (m, 8, aromaticH); 5.48 (s, 2H, ArCH₂ O); 3.80 (s, 3H, CO₂ CH₃).

Analysis: Calculated for C₁₅ H₁₃ BrO₃ : C, 56.09; H, 4.08; Br, 24.88.

Found: C, 56.12; H, 4.09; Br, 24.85.

(b) 2-(2-bromophenoxymethyl)benzoic acid

Methyl 2-(2-bromophenoxymethyl) benzoate (38 g) was refluxed in amixture of 100 mL of 10% aqueous sodium hydroxide and 200 mL of methanolfor three hours. The reaction mixture was concentrated under reducedpressure and water was added to the residue. The mixture was thenacidified with concentrated hydrochloric acid. Extraction of the cooledacidic solution with ethyl acetate and then concentration of the organiclayer gave 2-(2-bromophenoxymethyl)benzoic acid (30 g), mp 175°-177° C.pmr (CDCl₃) δ: 6.79-8.02 (m, 8H, aromatic H); 5.53 (s, 2H, ArCH₂ O).

Analysis: Calculated for C₁₄ H₁₁ BrO₃ : C, 54.74; H, 3.61; Br, 26.02.

Found: 54.64; H, 3.61; Br, 26.14.

(c) 4-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-one

A suspension of 2-(2-bromophenoxymethyl)benzoic acid (18.8 g, 0.06 mole)in 100 mL of trifluoracetic anhydride containing ten drops of borontrifluoride-ether complex was refluxed for four hours. The mixture waspoured into ice water and then extracted with diethyl ether.Concentration of the ether solution under reduced pressure gave the pureproduct (9.2 g), mp 127°-130° C. pmr (CDCl₃) δ: 7.28-8.19 (m, 76H,aromatic H); 6.99 (t, 1H, H2); 5.30 (s, 2H, ArCH₂ O).

Analysis: Calculated for C₁₄ H₉ BrO₂ : C, 56.16; H, 3.14; Br, 27.64.

Found: C, 58.19; H, 3.18; Br, 27.68.

(d)(E)/(Z)-3-(4-Bromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylaminehydrochloride

Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromidehydrobromide (22.5 g, 0.04 mole) was suspended in 550 mL of drytetrahydrofuran, and 55 mL of a solution of n-butyl lithium in hexane(1.6M) was added dropwise at 0° C. under a nitrogen atmosphere during a30-minute period. After an additional ten minutes,4-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (9.2 g, 0.03 mole) in 100mL of dry tetrahydrofuran was added slowly to the deep red solution andthe reaction mixture was then refluxed for 18 hours. The reactionmixture was poured into ice water, and the mixture was extracted withethyl ether. The ether layer was concentrated under reduced pressure andthe residue was suspended in water and then acidified with 6Nhydrochloric acid. The acidic aqueous layer was washed with hexane andthen was concentrated to give a gummy residue. It was chromatographed ona silica gel column (Waters Associates - Prep 500) with ethylacetate/methanol (8:2) to give 5.2 g of product as a mixture ofZ/E-isomers (approximately 95:5), mp>200° C. (grad. dec.). pmr (CDCl₃)δ: 7.56 (dd, 1H, H₃); 7.30-7.42 (m, 4H, aromatic H); 7.20 (dd, 1H, H₁);6.92 (t, 1H, H₂); 5.72 (t, 1H, CH═); 5.32 (br s, 2H, CH₂ O); 3.20 (t,2H, CH₂ N); 2.68 (m, 2H, CH₂); 2.70 (s, 6H, N(CH₃)₂); 5% of (E)-isomerby δ6.08 (t, 1H, CH═) and 2.64 (s, 6H, N(CH₃)₂).

Analysis: Calculated for C₁₉ H₂₀ BrNO.HCl.0.4 H₂ O: C, 56.78; H, 5.47;N, 3.48.

Found: C, 56.93; H, 5.30; N, 3.51.

EXAMPLE 8

(E)/(Z)-1-[2-(4-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-ethyl]pyrrolidine(Compound J)

Anhydrous 2-(N-pyrrolidinyl) ethyltriphenylphosphonium bromide (20 g, 45mmole), 45 mmole of n-butyl lithium in hexane (1.6M), and4-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 35 mmole) werereacted in 550 mL dry tetrahydrofuran by the procedure in Example 1,Step a. This offered a (Z)/(E) (60:40) isomeric product as a light brownoil. pmr (DMSO-d₆) δ: 7.28-7.56 (m, 5H, aromatic H); 7.15-7.26 (2 dd,1H, H₁); 6.88 (t, H₃ of 60% Z); 6.84 (t, H₃ of 40% E); 6.16 (t, CH═ of40% E) : 5.86 (t, CH═ of 60% Z) ; 5.30 (br s, 2H, ArCH₂ O); 2.28-2.54(m, 6H, N(CH₂)₃); 1.66 (m, 4H, 2CH₂).

Analysis: Calculated for C₂₀ H₂₀ BrNO: C, 64.87; H, 5.44; N, 3.78; Br,21.58.

Found: C, 64.84; H, 5.46; N, 3.77; Br, 21.68.

EXAMPLE 9

(E)/(Z)-3-(8-Bromo-6, 11-dihydrodiebenz[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylamine (Compound L)

(a) 8-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-one

Phenol (8 g, 85 mmole) and potassium carbonate (11.7 g, 85 mmole) in 150mL of N,N-dimethylformamide was reacted with methyl 4-bromo-α-bromo-2-toluate (20 g, 65 mmole) by the procedure of Example 6, step a andfollowed with alkaline hydrolysis by the procedure of Example 6, step bto give the crude 4-bromo-2-(phenoxymethyl)benzoic acid (13 g) which wasused without further purification.

The crude 4-bromo-2-(phenoxymethyl) benzoic acid (13 g, 42 mmole) wascyclized in 50 mL of trifluroacetic anhydride containing 1 mL of borontrifluorideether complex by the procedure of Example 6, step c. Thesolid was collected by filtration and washed with water to give 11.9 gof the tricyclic ketone, m.p. 125°-126° C. pmr (CDCL₃) δ: 8.17-8.30 (m,1H, H₁), 6.99-7.86 (m, 6H, aromatic H), 5.14 (s, 2H, ArCH₂ O) .

Analysis: Calculated for C₁₄ H₉ BrO₂ : C, 58.16; H, 3.14; Br, 27.64.

Found: C, 58.15; H, 3.17; Br, 27.73.

(b) (E)/(Z)-3-(8-Bromo-6 ,11-dihydrodibenz[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylamine

Anhydrous 3-(dimethylamino) propyltriphenylphosphonium bromidehydrobromide (24.5 g, 48 mmole), 96 mmole of n-butyl lithium in hexane(1.6M), and 8-bromo-6,11-dihydrodibenz [b, e]oxepin-11-one (10 g, 34.6mmole) were reacted in 580 mL dry tetrahydrofuran by the procedure ofExample 1, Step a. This provided an E/Z (1:3.5) isomeric mixture ofbromoamines. Recrystallization of the mixture from diethyl ether gave0.17 g of Z-isomer and 1.8 g of an E/Z (1:4) (assayed by HPLC on C18)isomeric mixture. pmr (Z-isomer) (CDCl₃) δ: 7.38-7.44 (m, 2H, H₇ andH₉); 7.13-7.18 (m, 3H, aromatic H); 6.84-6.93 (m, 2H, H₂ and H₄); 5.70(t, 1H, CH═); 5.15 (br s, 2H, ArCH₂ O); 2.55 (q, 2H, CH₂); 2.43 (t, 2H,NCH₂); 2.22 (s, 6H, NMe₂).

Analysis: Calculated for C₁₉ H₂₀ BrNO: C, 63.70; H, 5.63; N, 3.91.

Found (Z-isomer): C, 63.85; H, 5.65; N, 3.92.

EXAMPLE 10

(E)/(Z)-3-(9-Bromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylamine(Compound C)

Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromidehydrobromide (35 g, 69 mmole), 100 mmole of n-butyl lithium in hexane(1.6M), and 9-bromo-6, 11-dihydrodibenz[b,e]oxepin-11-one (20 g, 69mmole) were reacted in 750 mL dry tetrahydrofuran by the procedure ofExample 1, Step a. Recrystallization of the mixture fromchloroform/carbon tetrachloride gave 6.7 g of the product (Z:E=93.7) asits hydrochloride salt, melting range 85°-88° C. pmr (CDCl₃) δ:6.94-7.46 (m, 7H, aromatic), 6.04 (t, CH= of 7% E), 5.64 (t, CH=of 93%Z), 5.15 (br s, 2H, CH₂ O), 3.07 (m, 4H, NCH₂ CH₂), 2.75 (s, 6H, NMe₂).

Analysis: Calculated for C₁₉ H₂₀ BrNO.2.0 HCl.0.3 H₂ O: C, 52.27; H,5.22; N, 3.21.

Found: C, 52.28; H, 5.23; N, 3.18.

EXAMPLE 11

(E)/(Z)-1-[3-(9-Bromo-6,11-dihydrodibenz-[b,e]oxepin-11-ylidene)propyl]pyrrolidine(Compound M)

Anhydrous 3-(N-pyrrolidinyl)propyltriphenylphosphonium bromidehydrobromide (40 g, 0.08 mole), 0.16 mole of n-butyl lithium in hexane(1.6M), and 9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (20 g, 0.07mole) were reacted in 900 mL dry tetrahydrofuran by the proceduredescribed in Example 1, Step a. This provided 8.15 g of Z/E (5:1)mixture of 9-bromopyrrolidine which was converted to its hydrochloridesalt. The isomeric mixture was washed with hot ethyl acetate to give 6.0g of the product (Z:E =93:7) as a white solid, m.p. 214°-217° C. pmr(DMSO-d₆) δ: 6.94-7.56 (m, 6 H, aromatic H) , 6.86 (dd, H₄ of 93% Z),6.14 (dd, H4 of 7% E), 6.08 (t, CH═ of 7% E), 6.08 (t, CH═ of 7% E),5.76 (t, CH═ of 93% Z), 5.20 (br s, 2H, ArCH₂ O), 1.90-3.32 (m, 12H,6CH₂) .

Analysis: Calculated for C₂₁ H₂₂ BrNO.1.6 HCl: C, 56.98; H, 5.37; N,3.16.

Found: C, 56.89,; H, 5.32; N, 3.05.

EXAMPLE 12 (E)/(Z)-3-(2,9-Dibromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)-N,N-dimethylpropylamine (Compounds V and U)

(a) Methyl 5-bromo-2-(4-bromophenoxymethyl)benzoate

To a mixture of 4-bromophenol (50 g, 0.29 mole) and sodium hydride (14g, 0.36 mole) in 500 mL of N,N-dimethyl formamide was addedα-5-dibromo-2 -toluate (74 g, 0.24 mole). The reaction mixture wasstirred at 40° C. for 18 hours. The mixture was poured into ice waterand the solids were collected by filtration and washed with water togive the product (90 g). Analytical sample was obtained byrecrystallization from ethyl acetate, mp 101°-102° C. pmr (DMSO-d₆) δ:6.90-8.01 (m, 7H, aromatic H) , 5.35 (s, 2H, ArCH₂ O), 3.81 (s, 3H, CO₂CH₃) .

Analysis: Calculated for C₁₅ H₁₂ Br₂ O₃.0.20 EtoAc: C, 45.43; H, 3.28;Br, 38.26.

Found: C, 45.42; H, 3.10; Br, 38.61.

(b) 5-Bromo-2-[4-bromophenoxymethyl)benzoic acid

Methyl 5-bromo-2-(4 -bromophenoxymethyl)benzoate (90 g, 0.23 mole) wasrefluxed in a mixture of 100 mL of 10% sodium hydroxide and 200 mL ofmethanol for three hours. The reaction mixture was concentrated underreduced pressure and water was added to the residue. The mixture wasacidified with concentrated hydrochloric acid. A solid was precipitatedand collected as the acid product (80 g). mp 214°-215° C. pmr (DMSO-d₆)δ: 6.76-8.01 (m, 7H, aromatic H), 5.38 (s, 2H, ArCH₂ O).

(c) 2,9-Dibromo-6,11-dihydrodibenz[b,e]-oxepin-11-one

A solution of 5-bromo-2-(4-bromophenoxymethyl)benzoic acid (100 g, 0.26mole), and trifluoroacetic anhydride (160 mL) in one liter of methylenechloride containing 20 drops of boron trifluoride-ether complex wasrefluxed for three hours. The mixture was poured into ice water and thenextracted with diethyl ether. Concentration of ether solution underreduced pressure and chromatography of the residue on a silica gelcolumn (Waters Associates, Prep 500) with hexane/ethyl acetate (9:1)gave the ketone (45 g) mp 193°-194° C. pmr (DMSO-d₆) δ: 8.12 (d, J=2.7Hz, 1H, H₄) , 7.27-7.91 (m, 4H, aromatic H) , 7.10 (d, J=8.8 Hz, 1H,H₄), 5.32 (s, 2H, ArCH₂ O).

Analysis: Calculated for C₁₄ H₈ Br₂ O₂ : C, 45.69; H, 2.19; Br, 43.42.

Found: 45.49; H, 2.22; Br, 43.27.

(d) (E)/(Z) -3-(2,9-Dibromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidine)-N,N-dimethylpropylamine

Anhydrous 3-(dimethylamino) propyltriphenylphosphonium bromidehydrobromide (27 g, 0.05 mole), 0.1 mole of n-butyl lithium in hexane(1.6M), and 2,9-dibromo-6,11-dihydrodibenz [b,e]oxepin-11-one (15 g,0.04 mole) were reacted in 650 mL dry tetrahydrofuran by the procedureof Example 1, Step a. This provided an (E)/(Z) isomeric mixture ofdibromoamine. Separation of this mixture by a silica gel column (WatersAssociates - Prep 50) with ethyl acetate/methanol (9:1) offered theZ-isomer (5.4 g). mp 87°-88 ° C., pmr (DMSO) δ: 7.31-7.54 (m, 5H,aromatic H), 6.78 (d, J=8.9 Hz, 1H, H₄), 5.77 (t, 1H, CH═), 5.15 (br s,2H, ArCH₂ O), 2.40 (m, 4H, 2 CH₂), 2.10 (s, 6H, N(CH₃)₂). And a Z/Emixture (30:70) which was converted to its hydrochloride salt by addingone equivalent hydrochloric acid (0.18 g), mp 113°-115° C. pmr (DMSO-d₆)δ: 7.28-7.78 (m, 5H, aromatic H), 6.82 (d, J=8.8 Hz, H4 of 30% Z), 6.71(d, J=8.8 Hz, H₄ of 70% E), 6.04 (t, CH═ of 70% E), 5.76 (t, CH═ of 30%Z), 4.90-5.50 (m, 2H, ArCH₂ O), 2.30-3.19 (m, 10H, 2 CH₂ and N(CH₃)₂).

Analysis: Calculated for C₁₉ H₁₉ Br₂ NO: C, 52.20; H, 4.28; N, 3.20; Br,36.55.

Found (Z-isomer): C, 52.40; H, 4.40; N, 3.29; Br, 36.39.

Calculated for C₁₉ H₁₉ Br₂ NO.HCl: C, 48.18; H, 4.26; N, 2.96.

Found (Z/E=30:70): C, 48.57; H, 4.66; N, 2.68.

EXAMPLE 13

(E)/(Z)-1-[3-(2,9-Dibromo-6,11-dihydrodibenz-[b,e]oxepin-11-ylidene)propyl]pyrrolidine(Compounds R and O)

Anhydrous 3-(N-pyrrolidinyl) propyltriphenylphosphonium bromidehydrobromide (47 g, 0.08 mole), 0.20 mole of n-butyl lithium in hexane(1.6M), and 2,9-dibromo-6,11-dihydrodibenz [b,e]oxepin-11-one (25 g,0.07 mole) in one liter of dry tetrahydrofuran by the procedure ofExample 1, Step a. The crude product was chromatographed on a silica gelcolumn (Waters Associates -Prep 500) with ethyl acetate/emthanol (95:5)to give the product as 98% pure Z-isomer (0.30 g) , mp 102°-103° C. pmr(DMSO-d₆) δ: 7.31-7.54 (m, 5H, aromatic H), 6.79 (d, J=7.8 Hz, H₄ of 98%Z) , 6.67 (d, J=7.8 Hz, H₄ of 2% E) , 6.11 (t, CH═ of E) , 5.78 (t, CH═of 98% Z) , 2.34-2.56 (m, 8H, CH₂ and NHCH₂), 1.63 (m, 4H, 2CH₂). And itgave another batch of the product as 90% pure E-isomer (0.18 g), mp115°-16° C., pmr (DMSO) δ: 7.71-7.68 (m, 5H, aromatic H), 6.80 (d, J=7.8Hz, H₄ of 10% Z) , 6.70 (d, J=7.8 Hz, H₄ of 90% E), 6.10 (t, CH═ of 90%E), 5.81 (t, CH═ of 10% Z), 2.26-2.40 (m, 8H, CH₂ and 3NCH₂), 1.60 (m,4H, 2CH₂) .

Analysis: Calculated for C₂₁ H₂₁ Br₂ NO: C, 4.45; H, 34.57; N, 3.02, Br,34.50.

Found (Z/E=98:2): C, 54.51; H, 4.59; N, 3.01; Br, 34.45.

Found (Z/E=10:90): C, 54.51; H, 4.57; N, 3.04; Br, 34.40.

EXAMPLE 14

(Z)-1-[2-(6,11-Dihydrodibenz[b,e]-oxepin-11-ylidene)ethyl]pyrrolidine(Compound H)

A solution of n-butyl lithium in hexane (1.6M, 3 mL) was added dropwiseto a solution of 1.5 g pure(Z)-1-[2-(2-bromo-6,11-dihydrodibenz[b,e]-oxepin-11-ylidene)ethyl]pyrrolidine in 100 mL of dry tetrahydrofuran at -70° C. under anitrogen atmosphere. After the yellowish orange solution was stirred at-70° C. for ten minutes, gaseous carbon dioxide was bubbled through thereaction medium to give a pale yellow solution. The solution was allowedto warm gradually to room temperature and was then concentrated underreduced pressure. None of the carbonylated products were able to bedetected by HPLC on C18. The foamy residue was suspended in water, andthe solids were collected by filtration. The solid obtained wasrecrystallized from water to give debrominated Z-isomer (0.08 g), m.p.203°-205° C. pmr (CD₃ OD) δ: 7.30-7.40 (m, 4H, aromatic H); 7.24-7.27(m, 1H, aromatic H); 6.90-7.07 (m, 3H, aromatic H); 5.84 (t, 1H, CH═);5.25 (br s, 2H, ArCH₂ O); 4.19 (d, J=6.5 Hz, 2H, NCH₂ C═); 3.30 (m, 4H,2NCH₂); 2.04 (m, 4H, 2CH₂).

Analysis: Calculated for C₂₀ H₂₁ NO.1.25 H₂ O: C, 68.56; H, 7.05; N,4.00.

Found: C, 68.62; H, 6.94; N, 3.98.

EXAMPLE 15 In Vitro Cytotoxicity of Potentiating Agents in ChineseHamster Ovary Cells

Chinese hamster ovary (CHO) tissue culture cells were obtained from Dr.Vic Ling, Princess Margaret Hospital, Toronto, Canada. The parental cellline (AuxB1) and a multidrug resistant line (C5S32) having an amplifiedform of the MDR drug transport protein were plated into 96-wellmicrotitre culture dishes at 250 or 500 cells per well in minimalessential medium, type alpha, 10% fetal calf serum and incubated in 95%oxygen/5% carbon dioxide for 48 hours. After this period, the medium waschanged and one-half of the culture was treated with Actinomycin D (ActD) (0.01 μM for AuxB1 cells and 0.5 μM for C5S32 cells). C5S32 cells areabout 200-fold resistant to Actinomycin D compared to the parental AuxB1cell line. In addition to Act D some of the cultures also received adose of the potentiating agent at 1 and 10 μM. Thus, four conditionswere tested in each screening assay: untreated cells in medium alone,cells receiving Act D alone, cells incubated with the potentiating agentalone, and cells incubated with a combination of Act D and thepotentiating agent. Both the parental and mdr cell lines were treatedwith these four conditions simultaneously. Each experimental conditionreported below is based on the average absorbance from eight replicatesamples. The incubation with Act D and the test drug continued for 96additional hours, after which 0.5 mg/ml MTT dye was added to thecultures and allowed to incubate for three hours. The cells weresolubilized by addition of DMSO and the absorbance at 570 nm wasmonitored. The absorbance is directly related to the number of survivingcells in the culture dish.

In Table 1 below, the absorbance was normalized so that cytotoxicity ofthe potentiating agent could be evaluated. Untreated cultures were givena value of 1.00 and the cultures receiving 1 and 10 μM of thepotentiating agent are reported as a fraction of this value. To evaluatethe compounds for inducing synergism with Actinomycin D, the absorbancevalues of cultures receiving Act D alone were assigned a value of 1.00and cultures receiving the combination of Act D and potentiating agentAct D are reported as a fraction of this control. In most experiments,this concentration of Act D gave a reduction in cell number 10-20% belowthe value of completely untreated cultures.

                  TABLE 1                                                         ______________________________________                                        In Vitro Cytotoxicity of Potentiating                                         Agents in Chinese Hamster Ovary Cells                                                    Wildtype    Drug Resistant                                                    AUXB1       C5S32                                                  Compound                                                                              Dose     0       +ACT D  0     +ACT D                                 ______________________________________                                        (A)     1     μM  1.00  1.00    0.85  0.71                                         10    μM  1.00  0.99    0.42  0.22                                 (B)     1     μM  0.98  1.00    0.83  0.82                                         10    μM  0.87  0.62    0.55  0.37                                 (C)     1     μM  1.00  0.92    1.00  0.90                                         10    μM  0.92  0.95    1.00  0.54                                 (D)     1     μM  1.00  1.00    0.89  0.71                                         10    μM  1.00  0.99    0.34  0.31                                 (E)     1     μM  1.00  1.00    0.85  0.66                                         10    μM  1.00  0.98    0.48  0.35                                 (F)     1     μM  1.00  0.96    0.82  0.68                                         10    μM  0.88  0.64    0.28  0.19                                 (G)     1     μM  1.00  1.00    0.54  0.47                                         10    μM  1.00  0.65    0.15  0.10                                 (H)     1     μM  1.00  1.00    0.82  0.95                                         10    μM  0.94  0.92    0.53  0.51                                 (I)     1     μM  0.90  0.89    0.95  0.77                                         10    μM  0.92  0.21    1.00  0.36                                 (J)     1     μM  1.00  0.90    0.80  0.66                                         10    μM  1.00  0.83    0.29  0.12                                 (K)     1     μM  0.83  0.82    1.00  0.79                                         10    μM  0.87  0.03    1.00  0.28                                 (L)     1     μM  0.83  0.88    0.92  0.85                                         10    μM  0.81  0.60    0.99  0.42                                 (M)     1     μM  0.79  0.88    0.86  0.83                                         10    μM  0.84  0.47    1.00  0.35                                 (N)     1     μM  0.86  0.85    1.00  0.85                                         10    μM  0.83  0.46    0.80  0.33                                 (O)     1     μM  1.00  1.00    0.48  0.58                                         10    μM  0.93  0.90    0.35  0.38                                 (P)     1     μM  1.00  1.00    0.61  0.70                                         10    μM  1.00  1.00    0.31  0.38                                 (Q)     1     μM  0.97  1.00    0.53  0.69                                         10    μM  0.93  1.00    0.33  0.37                                 (R)     1     μM  0.99  1.00    0.50  0.52                                         10    μM  0.95  0.93    0.11  0.11                                 (S)     1     μM  0.91  0.99    1.00  0.94                                         10    μM  0.88  0.64    1.00  0.58                                 (T)     1     μM  1.00  0.95    1.00  1.00                                         10    μM  1.00  0.70    1.00  0.53                                 (U)     1     μM  0.84  0.78    0.94  0.93                                         10    μM  0.79  0.53    0.74  0.24                                 (V)     1     μM  0.86  0.85    0.91  0.87                                         10    μM  0.77  0.53    0.75  0.20                                 (W)     1     μM  1.00  0.85    0.98  0.86                                         10    μM  1.00  0.81    0.55  0.48                                 ______________________________________                                    

EXAMPLE 16 In Vitro Cytotoxicity of Potentiating Agents in Human KBEpidermoid Carcinoma Cells

The procedure for assaying the cytotoxicity of potentiating agents withhuman KB epidermoid carcinoma cells is essentially the same as the assayprocedure described above for use with Chinese hamster ovary cells. Inbrief, KB 3-1 (wt) and KB V-1 (mdr) cells are plated at 500 cells/wellin 96-well culture plates in Dulbecco's modified eagle medium,supplemented with 10% fetal calf serum. After 48 hours of incubation at37° C., the media is changed and cells are treated with actinomycin D at0.1 nM (3-1) or 20 nM (V-1). The test potentiating agent is introducedto one-half the untreated cultures and one-half the Act D treatedcultures at 1 and 10 μM. After 96 hours of additional incubation at 37°C., 0.5 mg/ml MTT dye is added, the cells are incubated for three hours,after which the cells are dissolved in DMSO, and the absorbance is thenread at 570 nm. The data is given in Table 2 below.

                  TABLE 2                                                         ______________________________________                                        In Vitro Cytotoxicity of Potentiating Agents                                  in Human KB Epidermoid Carcinoma Cells                                                   Wildtype    Drug Resistant                                                    KB 3-1      KB V-1                                                 Compound                                                                              Dose     0       +ACT D  0     +ACT D                                 ______________________________________                                        (A)     1     μM  0.99  0.88    1.00  0.99                                         10    μM  0.98  1.00    0.75  0.21                                 (B)     1     μM  1.00  1.00    1.00  1.00                                         10    μM  0.83  0.91    0.44  0.01                                 (C)     1     μM  1.00  0.78    1.00  0.97                                         10    μM  1.00  0.75    0.34  0.36                                 (D)     1     μM  0.88  0.86    0.75  0.78                                         10    μM  0.51  0.65    0.36  0.01                                 (E)     1     μM  0.89  0.85    0.88  0.74                                         10    μM  0.89  0.77    0.45  0.01                                 (F)     1     μM  0.84  0.86    0.80  0.77                                         10    μM  0.78  0.68    0.59  0.12                                 (G)     1     μM  0.87  0.80    0.86  0.91                                         10    μM  0.74  0.87    0.70  0.35                                 (I)     1     μM  0.99  0.99    0.98  0.95                                         10    μM  0.30  0.40    0.34  0.04                                 (J)     1     μM  0.89  0.85    0.88  0.74                                         10    μM  0.80  0.77    0.45  0.01                                 (K)     1     μM  0.85  0.77    0.86  0.88                                         10    μM  1.00  0.03    0.08  0.13                                 (L)     1     μM  1.00  1.00    0.98  1.00                                         10    μM  0.97  0.94    0.51  0.23                                 (M)     1     μM  1.00  1.00    0.95  1.00                                         10    μM  0.96  1.00    0.65  0.31                                 (O)     1     μM  0.79  0.81    0.74  0.78                                         10    μM  0.64  0.73    0.07  0.06                                 (P)     1     μM  0.65  0.72    0.73  0.72                                         10    μM  0.65  0.71    0.52  0.58                                 (Q)     1     μM  0.92  0.91    0.86  0.83                                         10    μM  0.77  0.78    0.80  0.65                                 (R)     1     μM  0.78  0.84    0.87  0.90                                         10    μM  0.36  0.34    0.06  0.02                                 (S)     1     μM  0.77  0.79    0.89  0.84                                         10    μM  0.67  0.72    0.72  0.48                                 (T)     1     μM  0.86  0.90    0.96  0.92                                         10    μM  0.81  0.83    0.84  0.64                                 ______________________________________                                    

EXAMPLE 17 Formulations

In the formulations of this Example the active compound is a compound ofFormula (I) described hereinbefore.

    ______________________________________                                        (A) - Injectable                                                                              Amount Per                                                    Ingredient      Ampoule                                                       ______________________________________                                        Active Compound 1.0 mg                                                        Water for Injections                                                                          1.0 mL                                                        ______________________________________                                    

The finely ground active compound is dissolved in the water forinjections. The solution is filtered and sterilized by autoclaving.

    ______________________________________                                        (B) - Syrup                                                                                       Amount Per                                                Ingredient          Ampoule                                                   ______________________________________                                        Active Compound     1.0     mg                                                Ethanol             0.3     mg                                                Sucrose             2.0     mg                                                Methylparaben       0.5     mg                                                Sodium Benzoate     0.5     mg                                                Cherry Flavour      q.s.                                                      Colouring           q.s.                                                      Water               Q.S. to 5.0 mL                                            ______________________________________                                    

Ethanol, sucrose, sodium benzoate, methylparaben, and flavouring arecombined in 70% of the total batch quantity of water. Colouring and theactive compound are dissolved in the remaining water, then the twosolutions are mixed and clarified by filtration.

    ______________________________________                                        (C) - Tablet                                                                                       Amount Per                                               Ingredient           Tablet                                                   ______________________________________                                        Active Compound      1.0     mg                                               Lactose              110.0   mg                                               Corn Starch,         2.5     mg                                               Pregelatinized                                                                Potato Starch        12.0    mg                                               Magnesium stearate   0.5     mg                                           

The active compound is finely ground and intimately mixed with thepowdered excipients lactose, corn starch, potato starch and magnesiumstearate. The formulation is then compressed to afford a tablet weighing126 mg.

    ______________________________________                                        (D) - Capsule                                                                                      Amount Per                                               Ingredient           Capsule                                                  ______________________________________                                        Active Compound      1.0     mg                                               Lactose              440.0   mg                                               Magnesium Stearate   5.0     mg                                               ______________________________________                                    

The finely ground active compound is mixed with the powdered excipientslactose and magnesium stearate and packed into gelatin capsules.

    ______________________________________                                        (E) - Nasal Spray                                                                                  Amount Per                                               Ingredient           100.0 mL                                                 ______________________________________                                        Active Compound      1       g                                                Sodium Chloride      0.8     g                                                Preservative         0.5     g                                                Purified Water       100.0   mL                                               ______________________________________                                    

The preservative is dissolved in warm purified water and after coolingto 25°-30° C. the sodium chloride and active compound are added. The pHis then adjusted to 5.5-6.5 and purified water is added to bring thefinal volume to 100.0 mL.

The foregoing Examples are illustrative of the present invention, andare not to be taken as restrictive thereof. The invention is defined bythe following claims, with equivalents of the claims to be includedtherein.

That which is claimed is:
 1. A method of increasing the sensitivity of atumor to an antineoplastic agent, which tumor is harbored in a subjectand which tumor is resistant to said antineoplastic agent, comprisingconcurrently administering to said subject an antineoplastic agent and apotentiating agent, said potentiating agent comprising a compound of theformula: ##STR4## wherein: R₁ is selected from the group consisting of--CH₂ CH₂ --, --CH₂ O--, --OCH₂ --, --NHCH₂ --, and --CH₂ NH--;X isselected from the group consisting of hydrogen and halogen; Y isselected from the group consisting of hydrogen and halogen; n is from 0to 3; each of p and q is from 1 to 4; and R₂ and R₃ are eachindependently selected from the group consisting of hydrogen and C₁₋₄alkyl, or together with the nitrogen atom form a nitrogen-containingheterocyclic ring having four to six ring members; or a pharmaceuticallyacceptable salt thereof, said potentiating agent being administered inan amount effective to increase the sensitivity of said tumor to saidantineoplastic agent.
 2. A method according to claim 1, wherein saidantineoplastic agent is administered to said subject parenterally andsaid potentiating agent is administered to said subject parenterally. 3.A method according to claim 1, wherein said antineoplastic agent isselected from the group consisting of vinca alkaloids,epipodophyllotoxins, anthracycline antibiotics, actinomycin D,plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B,emetine, maytansine, and amsacrine.
 4. A method according to claim 1,wherein said tumor is an adenocarcinoma.
 5. A method according to claim1, wherein said antineoplastic agent is a vinca alkaloid.
 6. A methodaccording to claim 1, wherein said antineoplastic agent is vincristine.7. A method according to claim 1, wherein R₁ in said potentiating agentis selected from the group consisting of --CH₂ O-- and --OCH₂ --.
 8. Amethod according to claim 1, wherein said said potentiating agent is(Z)-[2-(2-Bromo-6,11-dihydrodibenz[[b,e]oxepin-11-ylidene)ethyl]pyrrolidine.9. A method according to claim 1, wherein ;said antineoplastic agent isa vinca alkaloid, and wherein R₁ in said potentiating agent is selectedfrom the group consisting --CH₂ O-- and --OCH₂ --.
 10. A methodaccording to claim 9, wherein said vinca alkaloid is vincristine.
 11. Amethod according to claim 10, wherein said said potentiating agent is(Z)-[2-(2-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)ethyl]pyrrolidine.
 12. A pharmaceuticalformulation comprising, in a pharmaceutically acceptable carrier, atumor-inhibiting amount of an antineoplastic agent and a potentiatingagent in an amount effective to enhance the efficacy of saidantineoplatic agent, said potentiating agent comprising a compound ofthe formula: ##STR5## wherein: R₁ is selected from the group consistingof --CH₂ CH₂ --, --CH₂ O--, --OCH₂ --, --NHCH₂ --, and --CH₂ NH--;X isselected from the group consisting of hydrogen and halogen; Y isselected from the group consisting of hydrogen and halogen; n is from 0to 3; each of p and q is from 1 to 4; and R₂ and R₃ are eachindependently selected from the group consisting of hydrogen and C₁₋₄alkyl, or together with the nitrogen atom form a nitrogen-containingheterocyclic ring having four to six ring members; or a pharmaceuticallyacceptable salt thereof.
 13. A pharmaceutical formulation as claimed inclaim 12, wherein said antineoplatic agent is selected from the groupconsisting of vinca alkaloids, epipodophyllotoxins, anthracyclineantibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol,colchicine, cytochalasin B, emetine, maytansine, and amsacrine.
 14. Apharmaceutical formulation according to claim 12, wherein saidantineoplastic agent is a vinca alkaloid.
 15. A pharmaceuticalformulation according to claim 12, wherein said antineoplastic agent isvincristine.
 16. A pharmaceutical formulation according to claim 12,wherein R₁ in said potentiating agent is selected from the groupconsisting of --CH₂ O-- and --OCH₂ --.
 17. A pharmaceutical formulationaccording to claim 12, wherein said potentiating agent is(Z)-[2-(2-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)ethyl]pyrrolidine18. A pharmaceutical formulation according to claim 12, wherein saidantineoplastic agent is a vinca alkaloid, and wherein R₁ in saidpotentiating agent is selected from the group consisting of --CH₂ O--and --OCH₂ --.
 19. A pharmaceutical formulation according to claim 18,wherein said vinca alkaloid is vincristine.
 20. A pharmaceuticalformulation according to claim 19, wherein said potentiating agent is(Z)-[2-(2 -Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)ethyl]pyrrolidine.